Previous reports have indicated that fetal kidney cortex contains many trophic factors from the TGFb superfamily, such as GDNF, OPI and TGFb itself. These trophic factors have all been reported to be neuroprotective. We recently found that intracerebral administration of GDNF or implantation of fetal, but not adult kidney tissue, diminishes neocortical infarction after stroke in rats. Using homologous recombination, GDNFa receptor (GFRa1) deficient homozygous (-/-) and heterzygous (+/-) mice were generated and compared to their wildtype (+/+) litermates. The -/- mice died within 24 hours of birth with renal agenesis and enteric nervous system defects as have been previously reported. To evaluate the role of GFR a1 in neuroprotection, we pretreated adult chloral hydrate-anesthetized GFR-a1 +/- and +/+ mice with GDNF or fetal kidney tissue. We found that both pre-treatments decreased motor deficits induced by middle cerebral arterial ligation and reperfusion in +/+, but not in +/-, mice. The animals were subsequently sacrificed for TTC staining. We found that implantation of fetal rat kidney tissue decreased cortical infarction in +/+, but not in +/-, mice. Similar to fetal kidney grafting, local administration of GDNF also significantly reduced the incidence of severe infarction in +/+ mice, suggesting that the neuroprotective effect of GDNF in +/- mice, compared to -/- mice, is reduced. Taken together, our results indicate that the neuroprotection induced by fetal kidney grafting and GDNF administration may be derived from a similar mechanism and neuroprotectve actions of exogenous GDNF also require full levels of GFRa1 receptor expression. - GDNF, Stroke, Null-mutations